5-Aminothiazoles Reveal a New Ligand-Binding Site on Prolyl Oligopeptidase Which is Important for Modulation of Its Protein-Protein Interaction-Derived Functions

Henri T. Pätsi, Tommi P. Kilpeläinen, Mikael Jumppanen, Johanna Uhari-Väänänen, Pieter Van Wielendaele, Francesca De Lorenzo, Hengjing Cui, Samuli Auno, Janne Saharinen, Erin Seppälä, Nina Sipari, Juha Savinainen, Ingrid De Meester, Anne Marie Lambeir, Maija Lahtela-Kakkonen, Timo T. Myöhänen, Erik A.A. Wallén

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

A series of novel 5-aminothiazole-based ligands for prolyl oligopeptidase (PREP) comprise selective, potent modulators of the protein-protein interaction (PPI)-mediated functions of PREP, although they are only weak inhibitors of the proteolytic activity of PREP. The disconnected structure-activity relationships are significantly more pronounced for the 5-aminothiazole-based ligands than for the earlier published 5-aminooxazole-based ligands. Furthermore, the stability of the 5-aminothiazole scaffold allowed exploration of wider substitution patterns than that was possible with the 5-aminooxazole scaffold. The intriguing structure-activity relationships for the modulation of the proteolytic activity and PPI-derived functions of PREP were elaborated by presenting a new binding site for PPI modulating PREP ligands, which was initially discovered using molecular modeling and later confirmed through point mutation studies. Our results suggest that this new binding site on PREP is clearly more important than the active site of PREP for the modulation of its PPI-mediated functions.

Originalspråkengelska
TidskriftJournal of Medicinal Chemistry
Volym67
Nummer7
Sidor (från-till)5421–5436
ISSN0022-2623
DOI
StatusPublicerad - 2024
MoE-publikationstypA1 Tidskriftsartikel-refererad

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© 2024 American Chemical Society.

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